Propentofylline is a xanthine derivative that has been tested extensively in humans as a neuroprotective agent for treatment of Alzheimer""s Disease and vascular dementia. In clinical trials, propentofylline has been shown to be both safe and effective for the treatment of these neurodegenerative diseases (Mielke et al., Alzheimer Dis. Assoc. Disord., 1998, 12, S29-35; Rother et al., Dement. Geriatr. Cogn. Disord., 1998, 9, 36-43). The effects observed with propentofylline treatment include a reduction in the extent of brain neuropathology, an improvement in cognitive function, a decrease in activation of microglia, and inhibition of inflammatory processes. The drug is well absorbed and extensively metabolized following oral dosing (Kwon et al., Arch. Pharm. Res., 1998, 21, 698-702). The pharmacokinetic and pharmacodynamic profile of propentofylline have made it a promising therapeutic in the treatment of neurodegenerative diseases.
The pharmacological effects of propentofylline have been linked to inhibition of adenosine transport and inhibition of phosphodiesterase. Studies have also suggested this drug has effects to stimulate the synthesis and secretion of nerve growth factor, and can act as a transcriptional modulator and inducer of apoptosis in certain types of brain cells (Kamada et al., No To Shinkei, 1996, 48, 1022-1028). Propentofylline has also been shown to have a differential effect on the production of certain cytokines such as interleukin-6, interleukin-1 beta, and tumor necrosis factor alpha (Miki et al., Clin. Ther., 1991, 13, 747-753).
Chronic pain from nerve injury is a debilitating condition that affects millions of Americans. Such pain can occur as a result of cancer, multiple sclerosis, HIV-associated neuropathy, diabetic neuropathy, trigeminal neuralgia, postherpetic neuralgia (shingles), phantom limb pain, nerve injury due to trauma or surgery, and deafferentation pain. Most of these chronic pain syndromes are refractory to standard analgesics such as morphine and non-steroidal anti-inflammatory drugs. In addition, such drugs must be given in high doses such that they are associated with a variety of side effects that often limits the long-term use. Many of these side effects are life-threatening such as kidney toxicity and gastrointestinal distress in the case of the non-steroidal anti-inflammatory drugs and respiratory depression in the case of morphine. Clearly, there is a need to identify new compounds for treatment of chronic pain, in particular ones with a better therapeutic index (ratio of effective dose to toxic dose).
It has now been found that propentofylline, a drug shown to have a favorable safety profile in humans with neurodegenerative disease, has unexpected effects to decrease chronic neuropathic pain.
The present invention is a pharmaceutical composition containing propentofylline and methods for decreasing neuropathic pain.
Neuropathic pain, or chronic pain from nerve injury, is not only chronic and intractable, but debilitating, often causing severe physical, psychological and social distress. It has been found that propentofylline, a safe and effective drug for treatment of neurodegenerative diseases such as Alzheimer""s Disease, has a previously unrecognized effect to reduce chronic nerve pain.
Experiments were performed using a well-established animal model for chronic pain, spinal nerve transection in the rat. The model measures changes in mechanical allodynia, or an increased sensitivity following non-noxious stimulus, such as touch. Rats were injected intraperitdneally one day before and then daily for ten days following nerve transection. Results showed that there was a significant decrease in mechanical allodynia following treatment with propentofylline at doses of 1 and 10 mg/kg. The effect was dose-dependent, with larger reductions seen with higher doses of the drug.
The same model. was used with rats injected intrathecally with either saline or propentofylline (1 or 3 xcexcg), daily for 10 days. Again, there was a significant decrease in mechanical allodynia following treatment with propentofylline. The responses were also dose-dependent with the largest reduction seen at the highest dose tested.
These data demonstrate the efficacy of propentofylline to decrease neuropathic pain after both peripheral and central administration. As expected, the dose required to produce a reduction in pain responses in the animal was lower with central administration. In a preferred embodiment, propentofylline would be administered to an animal, including a human. The pain could be due to a variety of causes including but not limited to cancer, multiple sclerosis, low back pain associated with radiculopathy (root injury), HIV-associated neuropathy, diabetic neuropathy, trigeminal neuralgia, postherpetic neuralgia, phantom limb pain, or nerve injury due to surgery or trauma. The drug would be administered in a pharmaceutically acceptable carrier either orally, intravenously, intramuscularly, subcutaneously, by infusion pump implanted subcutaneously, intrathecally, or any other applicable route of administration that would deliver the drug to the desired site of action. One of skill would understand how to formulate and deliver propentofylline based on knowledge of the pharmacokinetics of the drug collected in patients treated for neurodegenerative diseases and the clinical studies that supported the development of the drug for neurodegenerative diseases. Propentofylline""s effects on chronic nerve pain will also be useful for designing studies to elucidate the mechanisms of chronic pain and potentially in the design of other novel compounds for treatment of chronic nerve pain.